Project Summary This application is in response to Notice of Special Interest: Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease NOT-AG-20-008. This proposal is a supplement to our current 1U01AA026917 study on ?Immunological Profiles and prognostic outcomes in patients with alcoholic hepatitis?. Here, we will extend our observation on alcohol and immune responses into its effect on cognitive function, notably Alzheimer's disease (AD). Current data suggest an important role of liver dysfunction in AD pathophysiological characteristics; however, the causality, the mechanism, and the pathways underlying these observations have not been elucidated. We thus hypothesized that ALD is an important pathological risk factor for AD due to ALD-associated metabolic alteration. We will address this knowledge gap and test our hypothesis by carefully examining the model systems of ALD in tgF344-AD (Tg) mutant rat that recapitulates the development of AD pathology and associated behavioral deficits. We will determine if the presence of ALD accelerates the AD pathophysiological characteristics. In this aim, WT and Tg rats will be fed with either ethanol or isocaloric liquid diet. Neurological pathology will be determine at 6 and 12 months. We will also determine if the presence of ALD affects the peripheral clearance of Amyloid ? (A?) by employing the rat models as well as human samples (liver and serum) from controls and those with alcoholic cirrhosis. The success of this supplemental proposal will expand the scope of our existing award that is not currently focused on AD to allow for future studies on ALD and brain (focusing on AD) axis.